EP2606975A2 - Système microfluidique à système de chargement de fluide dosé pour dispositif microfluidique - Google Patents

Système microfluidique à système de chargement de fluide dosé pour dispositif microfluidique Download PDF

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Publication number
EP2606975A2
EP2606975A2 EP12198735.8A EP12198735A EP2606975A2 EP 2606975 A2 EP2606975 A2 EP 2606975A2 EP 12198735 A EP12198735 A EP 12198735A EP 2606975 A2 EP2606975 A2 EP 2606975A2
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Prior art keywords
fluid
reservoir
microfluidic
microfluidic device
input mechanism
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EP12198735.8A
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German (de)
English (en)
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EP2606975A3 (fr
EP2606975B1 (fr
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Adrian Marc Simon Jacobs
Jason Roderick Hector
Benjamin James Hadwen
Campbell Donald Brown
Pamela Ann Dothie
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Sharp Life Science EU Ltd
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Sharp Corp
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • B01L3/502792—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics for moving individual droplets on a plate, e.g. by locally altering surface tension
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/045—Connecting closures to device or container whereby the whole cover is slidable
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/089—Virtual walls for guiding liquids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/02—Drop detachment mechanisms of single droplets from nozzles or pins
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B01L2400/0427—Electrowetting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0442—Moving fluids with specific forces or mechanical means specific forces thermal energy, e.g. vaporisation, bubble jet
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements

Definitions

  • the present invention relates to a system for loading fluid into a microfluidic device.
  • a system that controls the volume of fluid loaded into such a device It further to relates to a metered fluid loading system for Electrowetting-On-Dielectric (EWOD) devices.
  • EWOD Electrowetting-On-Dielectric
  • Microfluidics is a rapidly expanding field concerned with the manipulation and precise control of fluids on a small scale, often dealing with sub-microlitre volumes.
  • lab-on-a-chip the small nature of such devices allows rapid testing at point of need using much smaller clinical sample volumes than for traditional lab-based testing.
  • a microfluidic device can be identified by the fact that it has one or more channels (or more generally gaps) with at least one dimension less than 1 millimeter (mm).
  • Common fluids used in microfluidic devices include whole blood samples, bacterial cell suspensions, protein or antibody solutions and various buffers.
  • Microfluidic devices can be used to obtain a variety of interesting measurements including molecular diffusion coefficients, fluid viscosity, pH, chemical binding coefficients and enzyme reaction kinetics.
  • Other applications for microfluidic devices include capillary electrophoresis, isoelectric focusing, immunoassays, enzymatic assays, flow cytometry, sample injection of proteins for analysis via mass spectrometry, PCR amplification, DNA analysis, cell manipulation, cell separation, cell patterning and chemical gradient formation. Many of these applications have utility for clinical diagnostics.
  • Electrowetting on dielectric is a well-known technique for manipulating discrete droplets of fluid by application of an electric field. It is thus a candidate technology for microfluidics for lab-on-a-chip technology.
  • An introduction to the basic principles of the technology can be found in " Digital microfluidics: is a true lab-on-a-chip possible?", (R.B. Fair, Microfluid Nanofluid (2007) 3:245-281 ). This review notes that methods for introducing fluids into the EWOD device are not discussed at length in the literature. It should be noted that this technology employs the use of hydrophobic internal surfaces.
  • aqueous fluids In general, therefore, it is energetically unfavourable for aqueous fluids to fill into such a device from outside by capillary action alone. Further, this may still be true when a voltage is applied and the device is in an actuated state. Capillary filling of nonpolar fluids (e.g. oil) may be energetically favourable due to the lower surface tension at the liquid-solid interface.
  • nonpolar fluids e.g. oil
  • US20100282608 (Srinivasan et al.; published Nov. 11, 2010 ) describes an EWOD device comprising an upper section of two portions with an aperture through which fluids may enter. It does not describe how fluids may be forced into the device nor does it describe a method of measuring or controlling the inputted volume of such fluids.
  • Related application US20100282609 (Pollack et al.; published Nov. 11, 2010 ) does describe a piston mechanism for inputting the fluid, but again does not describe a method of measuring or controlling the inputted volume of such fluid.
  • a basic concept of the invention is an integrated fluid input mechanism for delivering a metered discrete volume of fluid into a microfluidic device.
  • Such a device may employ EWOD or AM-EWOD methods for fluid control.
  • the fluid input mechanism may operate by the displacement of a body of liquid or gas (e.g. air) to force fluid into the microfluidic device. In other embodiments the fluid input mechanism may operate by the expansion of a body of gas (e.g. air) to force fluid into the device.
  • a body of liquid or gas e.g. air
  • a body of gas e.g. air
  • the system may provide feedback via a fluid sensor, in order to verify that correct fluid input has occurred as part of an error detection method.
  • temperature feedback may provide the operator with analogue control of the volume of fluid input.
  • closure means are provided for closing and sealing the system following initial fluid application and prior to actuation of the fluid input mechanism.
  • a microfluidic system which includes a microfluidic device; and a metered fluid loading system formed integrally with the microfluidic device and configured to load a discrete metered volume of fluid into the microfluidic device upon actuation.
  • the metered fluid loading system includes a fluid input mechanism configured to actuate the metered fluid loading system.
  • the fluid input mechanism includes a bistable membrane actuator.
  • the bistable membrane actuator is configured to actuate the metered fluid loading system as a result of being deformed from a first bistable state to a second bistable state.
  • the fluid input mechanism includes a deformable membrane actuator.
  • the deformable membrane actuator is configured to actuate the metered fluid loading system as a result of being deformed from an undeformed state to a deformed state.
  • the fluid input mechanism further includes a limiter configured to limit an extent of deformation of the deformable membrane actuator.
  • the fluid input mechanism includes a heater which effects an expansion of a body of gas to actuate the metered fluid loading system.
  • the metered fluid loading system further including a temperature sensor as a feedback mechanism to control the expansion of the body of gas.
  • the metered fluid loading system includes a reservoir including an input channel through which the fluid is coupled from the reservoir to a gap of the microfluidic device.
  • the fluid input mechanism is operative to displace or expand a body of liquid or gas within the reservoir upon being actuated to force the fluid from the reservoir to the microfluidic device.
  • system further includes a seal for forming an airtight seal between the fluid input mechanism and the reservoir.
  • the fluid input mechanism is hinged to the reservoir permitting the fluid input mechanism to be opened and closed, and wherein when the fluid input mechanism is in an open position fluid which is to be loaded into the microfluidic device may be placed in the input channel, and when the fluid input mechanism is closed an airtight seal between the fluid input mechanism and the reservoir is formed.
  • system further includes a holding mechanism for holding the fluid input mechanism in the closed position.
  • the fluid input mechanism is coupled to the reservoir by sliding engagement.
  • the reservoir includes a plurality of input channels.
  • the reservoir further includes a vent column.
  • the microfluidic device includes sensing elements to detect a presence of the fluid loaded by the metered fluid loading system.
  • the microfluidic device includes at least one hydrophobic surface in contact with the fluid loaded in the microfluidic device.
  • the microfluidic device is configured to draw fluid from the fluid loaded in the microfluidic device by controlling a hydrophobicity of a surface of the microfluidic device.
  • the microfluidic device is an electrowetting on dielectric (EWOD) device.
  • EWOD electrowetting on dielectric
  • a front face of the reservoir is modified to prevent preferential wetting of the injected fluid laterally along the front face of the reservoir rather than being coupled to the gap of the microfluidic device.
  • an outlet of the reservoir to the microfluidic device includes an energy barrier configured to prevent fluid injected into the microfluidic device from returning to the reservoir.
  • the energy barrier is configured to permit discrete metered volumes of fluid to be loaded into the microfluidic device repeatedly in response to repeated actuations, while preventing the fluid from returning to the reservoir.
  • the microfluidic device includes a top substrate and a lower substrate with a gap therebetween and the reservoir is formed on one of the top or lower substrates which includes a hole aligned with the input channel.
  • the reservoir and the one of the top or lower substrates are formed of the same material. ( Fig. 20 )
  • the microfluidic device includes a wall between the top substrate and lower substrate and formed around the hole to ensure the fluid from the reservoir fills the microfluidic device in a preferred direction.
  • Figure 1 shows a known structure in cross-section of a microfluidic device such as an EWOD device.
  • the device includes a lower substrate 44 with a plurality of electrodes 38 (e.g., 38A and 38B) disposed upon it. These electrodes may have voltages applied directly or via a layer of thin-film electronics situated beneath the electrode layer (not shown) for example as in US application 12/830477 for an "Array Element Circuit and Active Matrix Device, filed on July 6, 2010 (published as US 2012/0006684 A1 on January 12, 2012 ).
  • the droplet 4, consisting of a conducting (e.g. ionic or polar) material is constrained in a plane between the lower substrate 44 and a top substrate 36.
  • the top substrate 36 has an electrode 28 thereon and a hydrophobic layer 26.
  • a suitable gap between the two substrates may be realised by means of a spacer 32, and a non-conducting liquid 34 (e.g. dodecane oil) may be used to occupy the volume not occupied by the droplet 4.
  • An insulator layer 20 disposed upon the lower substrate 44 separates the conductive electrodes 38A, 38B from a hydrophobic surface 16 upon which the droplet 4 sits with a contact angle ⁇ 6.
  • different voltages may be applied to different electrodes (e.g. electrodes 38A and 38B).
  • the hydrophobicity of the surface 16 can be thus be controlled, thus facilitating droplet movement in the lateral plane between the two substrates.
  • FIG. 2 illustrates an array of such elements.
  • a plurality of electrodes 38 is arranged in an electrode array 42, having M x N elements where M and N may be any number.
  • the droplet 4 is enclosed between the lower substrate 44 and the top substrate 36.
  • Such an array may be realised by direct connection or else facilitated by the aforementioned thin-film electronics allowing a large array of independently addressing elements.
  • FIGS 3a-3c illustrate a first embodiment of the invention.
  • a metered fluid loading system for inputting fluids, and namely a discrete metered volume of fluid, into the EWOD device.
  • the system preferably is formed integrally with the EWOD device, for example formed on the same lower substrate 44.
  • the entire assembly may be fabricated at low cost, for example by injection moulding.
  • the metered fluid loading system includes a reservoir 46 containing an input channel 48. Such a reservoir 46 is illustrated in projection view in Figure 4 .
  • the input channel 48 is configured to couple or inject the fluid from the reservoir 46 into a gap between the top substrate 36 and the lower substrate 44 of the EWOD device.
  • the metered fluid loading system further includes a fluid input mechanism, generally designated 50, which cooperates with the reservoir 46 and is in airtight contact with it.
  • the fluid input mechanism 50 operates so as to inject or otherwise cause the fluid 8 within the reservoir 46 to enter the EWOD device in the gap between the top substrate 36 and lower substrate 44.
  • the fluid input mechanism 50 may be of any form which causes fluid of known volume to enter the system. Specific examples are given below.
  • Figure 3a illustrates a first stage of the fluid input process where the fluid 8 substantially resides in the input channel 48 of the reservoir 46.
  • the fluid input mechanism 50 When the fluid input mechanism 50 is activated the fluid 8 is forcibly injected into the gap between top substrate 36 and lower substrate 44 as illustrated in Figure 3b .
  • a droplet 10 of the fluid 8 is drawn off from the main body of the fluid 8 by application of appropriate voltages on the electrode array 42 by virtue of the EWOD droplet control mechanism described previously (e.g., by application of different voltages to the electrodes 38 the hydrophobicity of the surface 16 can be controlled, thus facilitating movement of the fluid in the lateral plane between the substrates 36 and 44.
  • droplet 10 which is independent of the original body of fluid 8 and may be manipulated as needed for subsequent operations. It may be convenient for the inputted volume of fluid 8, seen in Figure 3b , to act as a master droplet from which a succession of smaller droplets 10 are drawn as needed, by the action of EWOD control.
  • the reservoir 46 may be formed of any suitable material that is compatible with the applied fluids. Compatibility implies that the material is not damaged or dissolved by the fluid 8, nor is the fluid contaminated by the material or substantially adheres to the material.
  • many engineering polymers may be used including PMMA (Poly(methyl methacrylate)), Nylon, PTFE (Polytetrafluoroethylene), PET (Polyethylene terephthalate), Polypropylene.
  • PMMA Poly(methyl methacrylate)
  • Nylon Poly(methyl methacrylate)
  • PTFE Polytetrafluoroethylene
  • PET Polyethylene terephthalate
  • Polypropylene Polypropylene. It may be advantageous that the shallow horizontal section of the input channel 48 is narrower than the gap between top substrate 36 and bottom substrate 44. This would help this feature to act as a capillary stop for fluid in the channel so that fluid does not enter the gap between top substrate 36 and bottom substrate 44 until the fluid input mechanism 50 is actuated. The manner in which the fluid input mechanism 50 may be
  • Figures 5a-5b illustrate a second embodiment of the invention providing a specific implementation of the fluid input mechanism generally shown as 50 in Figures 3a-3c .
  • the fluid input mechanism includes a bistable actuator 52 which may readily adopt either a first or second shape.
  • the first shape first bistable state
  • the second shape second bistable state
  • Such a bistable actuator 52 may be made, for example, of a suitable semi-flexible material such that on application of an external force it will deform from the first shape to the second shape.
  • Suitable materials include polystyrene copolymers such as High Impact Polystyrene. This force may be applied for example by an external rigid elongate element (not shown) pressed momentarily against the actuator 52.
  • Figure 5a illustrates the bistable actuator 52 in its first shape.
  • Figure 5b illustrates the bistable actuator 52 in its second shape following application of an external force to the top of the actuator.
  • the bistable actuator 52 works in cooperation with the input channel 48.
  • the first and second shapes must be chosen so as to tend to compress the air (or other suitable gas) in the input channel 48 following the change from first shape to second shape. As the total system is not sealed, this increase in air pressure cannot be sustained.
  • the air will, therefore, tend to approximately maintain its original volume and pressure, resulting in a translation of this volume of air and hence of the fluid 8 in the input channel 48 in response to the change in shape. This in turn forces the fluid 8 into the gap between top substrate 36 and lower substrate 44 thus achieving input of fluid 8 into the microfluidic device.
  • the volumes of the first and second shapes are known, the volume of input fluid 8 introduced into the microfluidic device via the gap between the top substrate 36 and the lower substrate 44 is known and fixed, and thus metered. This has the advantage that the volume is pre-defined at manufacture and not dependent on the motion or position of the element pressing on the actuator 52.
  • Figures 6a-6b illustrate a third embodiment of the invention providing a further implementation of the fluid input mechanism generally shown as 50 in Figures 3a-3c .
  • the fluid input mechanism includes a deformable membrane actuator 54 which is made of a suitable material capable of being deformed on application of an external force. This force may be applied for example by an external rigid elongate element (not shown) pressed against the actuator 54. In some applications it is useful if this deformation is reversible on removal of the force.
  • Suitable materials from which the actuator 54 may be made include elastomers such as silicone rubbers, natural rubber, nitrile rubbers, or fluoroelastomers such as copolymers of hexafluoropropylene (HFP) and vinylidene fluoride (VDF or VF2).
  • the actuator 54 is coupled to a reservoir 56 which differs from the reservoir of previous embodiments in that the top of the input channel 48 is structured as to form a limiter which limits the extent of deformation of the actuator 54.
  • the limiter is represented by a recessed step which prevents further deformation of the actuator 54.
  • Figure 6a shows the actuator 54 in an undeformed state.
  • Figure 6b shows the system during application of an external force and the actuator 54 is seen to have deformed in a manner than tends to compress the air in the input channel 48.
  • fluid 8 is forced into the gap between top substrate 36 and bottom substrate 44 thus achieving input of fluid 8 into the system
  • the known volume of this limiter feature sets a maximum value for the volume of input fluid, and thus again the loading of the fluid into the EWOD device is metered.
  • the external force applied to the bistable actuator 52 and deformable membrane actuator 54 of the embodiments of Figs. 5a , 5b and 6a , 6b , respectively, may be applied by mechanical or electromechanical means such as a solenoid or linear motor as will be appreciated. These may include sensing of the inputted fluid within the microfluidic device as a feedback to control operation of the mechanical or electromechanical means.
  • Figure 7 illustrates a fourth embodiment of the invention which represents an example implementation of any of the preceding embodiments. It shows a device controller box 60 which includes a box containing electronics to control the EWOD operation (or other microfluidic device) and may also include electronic or optical means for detection of the result of some assay carried out on the microfluidic device (for example a display with a glucose measurement is shown for illustration purposes). It may further be connected to a computer (not shown) for control and readout functions. There is further an actuation post 62 within an aperture of the controller box 60.
  • a device controller box 60 which includes a box containing electronics to control the EWOD operation (or other microfluidic device) and may also include electronic or optical means for detection of the result of some assay carried out on the microfluidic device (for example a display with a glucose measurement is shown for illustration purposes). It may further be connected to a computer (not shown) for control and readout functions.
  • Figure 8 illustrates a fifth embodiment of the invention providing a yet further implementation of the fluid input mechanism generally shown as 50 in Figures 3a-3c .
  • the reservoir 46 has a sealed non-deformable lid 70 serving as the fluid input mechanism together with a heater 72.
  • the heater 72 provides heating for example by electrical means.
  • the heater 72 may be attached to the lid 70, as illustrated, or else to the side of reservoir 46 or underside of substrate 44, in all cases to be in good thermal contact with the reservoir 46.
  • the heater may be realised by forming a thin conductor layer on the substrate 44 positioned under the reservoir 46.
  • a temperature sensor 74 may also be included as a feedback mechanism to ensure the desired temperature is reached. This has the advantage of allowing the user analogue control of the volume of fluid inputted.
  • the volume of fluid input is thus known and controllable by appropriate controller of the heater 72 so as to introduce a metered volume of fluid.
  • a gas other than air may occupy the fluid input channel.
  • FIG. 9 illustrates a sixth embodiment of the invention showing a mechanism for achieving this sealing which may be applied to any of the foregoing embodiments.
  • the fluid input mechanism 50 is attached to the reservoir 46 via a hinge 84 which allows said mechanism to rest in an open (as illustrated) or closed position.
  • the mechanism 50 also includes a clip 80 which mates with a matching structure (not shown) on the reservoir 46 to hold the mechanism 50 in a closed position.
  • a seal 82 for example a rubber or elastomer gasket, which may be attached to either the reservoir 46 (as illustrated) or the fluid input mechanism 50.
  • the fluid 8 may be placed in the input channel 48, for example by dispensing from a pipette. In the case of a blood sample alternatively it may be applied directly from a pricked fingertip.
  • the mechanism 50 is then clipped into a closed position forming a seal against the reservoir 46 via the seal 82.
  • Figures 10a-10b illustrate a seventh embodiment of the invention showing a further implementation of sealing the fluid input mechanism 50 (52,54,70) to the reservoir 46 in any of the foregoing embodiments.
  • the clip 80 there is a sliding hood 90 arranged around the mechanism 50 and a runner 92 formed on the side of the reservoir 46.
  • Figure 10a shows the system when the mechanism 50 is in the closed position. In this position the sliding hood 90 mates with the runner 92. The sliding hood may then be moved into a second position, as shown in Figure 10b , which locks the mechanism 50 in place and seals it in place.
  • the sliding hood 90 it obscures the movable element of the mechanism 50 in its first position but reveals it in the second position. This helps prevent accidental actuation until the mechanism 50 is locked in place.
  • Figures 11a-11b illustrate an eighth embodiment of the invention showing a further implementation of sealing the fluid input mechanism to the reservoir 46 which may be utilized in conjunction with any of the foregoing embodiments.
  • the fluid input mechanism is a sliding fluid input mechanism 100 attached to the reservoir 46 via a runner (not shown) on the reservoir 46 so as to be in sliding engagement.
  • Figure 11 a shows the mechanism 100 where the fluid may be input. It then may be moved into a closed position (shown in Figure 11 b) forming a seal with the reservoir 46.
  • Figure 12 illustrates a ninth embodiment and show a means of combining the deformable membrane actuator 54 and seal 82 of the foregoing embodiments into one element 110.
  • This may have advantages in ease of manufacture and may be made of any suitable deformable material such as elastomer or silicone rubber as previously described.
  • Figures 12a and 12b show a top side and under side of such an element, respectively. It comprises a deformable membrane actuator sub-element 112 and seal sub-element 114.
  • This element may be further encased in a rigid housing (not shown) to form the fluid input mechanism 50 and seal 82 combined of embodiments in Figures 9-11 .
  • FIG. 1 An example of a reservoir 46 with two input channels 48 is shown in Figure 13 .
  • Figure 14 illustrates a tenth embodiment of the invention which has a different shape to the input channel and may be applied to any of the foregoing embodiments.
  • the previously described input channel 48 included a single vertical column connected to a shallow horizontal channel which brought fluid up to the gap between substrates 36 and 44.
  • the air that it displaces must be allowed to escape through the system.
  • the electrode array 42 may also include sensing elements which would detect the presence of the droplet 10. Further, such elements may measure the impedance of the fluid that is present (for example, as described in the aforementioned US application 12/830477 ). Use of such sensing elements would provide feedback, e.g., confirmation that filling had occurred correctly and serve as an error detection mechanism. For example, if filling of the fluid was insufficient or had failed entirely, then detection of this could be used to automatically trigger, or indicate to an operator, a repeat of the filling operation. In the case of multiple input channels being present where one was malfunctioning, an alternative channel could automatically be selected.
  • FIG 15 illustrates an eleventh embodiment of the invention showing an aerial view of a system similar to that of the embodiment of Figure 3 .
  • the electrode array 42 is shown in more detail. It may be advantageous that this array comprises a high resolution electrode array 130 and a low resolution electrode array 132 formed on the lower substrate 44.
  • the low resolution electrode array 132 (comprising larger electrode pads) may be used to draw out and control the relatively large droplets that are drawn directly from the reservoir 46. These electrodes provide a linear path to separate these droplets from the main body of fluid 8 in the reservoir 46 and transport them to the main high resolution electrode array 130.
  • elongate electrodes are positioned either side of the main path within the low resolution electrode array 132 to help prevent fluid accidentally spreading beyond the bounds of the path.
  • the high resolution array 130 (comprising smaller electrode pads) may then be preserved for splitting these droplets into sub-droplets and carrying out subsequent operations for example a chemical assay.
  • Figure 16 illustrates a twelfth embodiment of the invention which represents an example implementation of any of the preceding embodiments. It shows a reservoir 46 where the hydrophobicity of a front face 140 of the reservoir 46 has been modified.
  • the front face 140 represents the area of the reservoir 46 which is exposed to contact with the fluid injected into the microfluidic device.
  • the hydrophobicity of the front face 140 of the reservoir 46 can be modified to prevent preferential wetting of the injected fluid laterally along the front face of the reservoir 46 rather than being injected neatly into the microfluidic device (e.g., into the gap between the top substrate 36 and the lower substrate 44).
  • the degree of hydrophobicity required for the reservoir 46 is dependent upon the fluid being loaded or initially placed into the reservoir 46 while the degree of hydrophobicity required for the front face of the reservoir 46 is dependent upon the hydrophobicity of the microfluidic environment into which it the fluid is being injected and the properties of the injected fluid itself.
  • the main body of the reservoir 46 can be made from a material that is compatible with loading the input fluid easily into the reservoir (e.g. hydrophilic materials for hydrophilic input fluids) while the hydrophobicity of front face of the reservoir 46 can be modified to provide a surface which repels rather than attracts the input fluid enabling the liquid to be neatly injected into the microfluidic device.
  • the hydrophobicity of the front face of the reservoir may be modified by physical means, chemical means, by combining different polymers, or by other means.
  • a reservoir 46 required to load an aqueous droplet into a hydrophobic microfluidic device filled with a non-conducting liquid e.g. dodecane oil
  • a substantially hydrophilic material e.g. PMMA
  • a hydrophobic front face bonded to it e.g. PTFE
  • Figures 17a-17c illustrate a thirteenth embodiment of the invention providing a further implementation of injecting a discrete metered volume of fluid into a microfluidic device.
  • Figure 17a illustrates the first stage of the fluid input process where the fluid 8 substantially resides in the input channel 48 of the reservoir 46.
  • the input channel 48 of the reservoir has been modified as to create an energy barrier at an outlet 150 to the microfluidic device.
  • the fluid input mechanism 50 When the fluid input mechanism 50 is activated the metered volume of fluid 8 is forced through the energy barrier 150 into the gap between the top substrate 36 and lower substrate 44 as illustrated in Figure 17b .
  • the fluid input mechanism 50 is released.
  • the energy barrier 150 prevents the injected liquid returning to the reservoir 46 and thus preserves the discrete metered volume of fluid in the microfluidic device.
  • the entry is a non-return valve which produces a droplet 10 that is independent of the original body of fluid 8 and may be manipulated as needed for subsequent operations.
  • the energy barrier is created by modifying the hydrophobicity of the input channel of the reservoir at the outlet. Alternatively, it may be achieved through geometrical means by constraining the dimensions of the input channel at the outlet, or a combination of both. In some instances, it may be advantageous to have a hydrophobic layer 16 extend slightly underneath the loading block at the outlet to help create the energy barrier.
  • the front face of the reservoir 46 may be modified such as to provide an energy barrier and also prevent the injected fluid wetting the front face of the reservoir.
  • Figures 18a-18c illustrate a fourteenth embodiment of the invention providing an implementation of progressively adding discrete metered volumes of fluid to a droplet within a microfluidic device.
  • the input channel 48 of the reservoir 46 has been modified as to create an energy barrier 150 at the outlet by means described above.
  • Figure 18a shows a droplet 10 within a microfluidic device.
  • the fluid input mechanism 50 When the fluid input mechanism 50 is activated a metered volume of fluid is forced through the energy barrier 150 into the gap between the top substrate 36 and the lower substrate 44 as illustrated in Figure 18b .
  • the injected fluid makes contact and merges with droplet 10.
  • the input mechanism 50 is released.
  • the energy barrier prevents the original droplet and the additional volume of injected liquid from returning to the reservoir 46, thus creating a larger droplet 160 whose volume has increased by a metered amount.
  • the process can be repeated until the desired droplet volume has been reached.
  • a fluid input mechanism is described which is positioned so as to adjacent one edge of the top substrate and so fill fluid into the gap between substrates 36 and 44 at the edge.
  • fluid may also be filled or injected from above as illustrated in Figure 19 .
  • a hole 170 is formed in the top substrate 36 and the metered fluid loading system including the fluid input mechanism 50 and reservoir 46 is glued or otherwise attached to the outer surface of the top substrate 36 so as to be integral with the outer surface of the top substrate 36.
  • the input channel 48 is aligned with the hole 170 allowing for fluid input.
  • the hole 170 and reservoir 46 may be included instead on the lower substrate 44.
  • the hole 170 is formed for example by drilling or laser cutting. All previously described methods for actuating the fluid input mechanism 50 may similarly be applied in the case of filling from above.
  • Figure 20 shows a manufacturing variant on this embodiment which may provide an easier and cheaper manufacturing route.
  • the reservoir 46 and top substrate 36 are made from the same material (e.g., plastic) and formed as one unit 180. This may all be made as one piece by simple techniques such as injection moulding.
  • the reservoir 46 and lower substrate 36 are made from the same material and formed as one unit.
  • Figure 21 a differs from Figure 19 in that a wall 190 is formed around the hole within the device to ensure the fluid fills in a preferred direction. Such a wall 190 may fill the full gap between substrates or else part of the gap.
  • the shape and function of such a wall 190 is more easily seen in a top view shown in right hand side of Figure 21b which gives an illustrative example of such a wall 190 (fluid input mechanism and reservoir omitted for clarity).
  • the wall 190 may be formed on the inside of the top substrate 36 (or combined top substrate 180) by any suitable means for example by application and patterning of a suitable photoresist to form the appropriate shape (e.g. SU-8, Microchem corporation). This would then be over-coated with the hydrophobic layer 26 (not shown).
  • the microfluidic device described herein could form part of a complete lab-on-a-chip system as described in prior art.
  • the fluids input and manipulated in the device could be chemical or biological fluids, e.g. blood, saliva, urine, etc. or any test reagent, and that the whole arrangement could be configured to perform a chemical or biological test or to synthesize a chemical or biochemical compound.
  • a suitable liquid may also be employed. Suitable liquids include those which within the input channel remain separated from the fluid which is to be loaded into the microfluidic device.
  • microfluidic device could form a part of a lab-on-a-chip system. Such devices could be used in manipulating, reacting and sensing chemical, biochemical or physiological materials. Applications include healthcare diagnostic testing, chemical or biochemical material synthesis, proteomics, tools for research in life sciences and forensic science.

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JP5762389B2 (ja) 2015-08-12

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